Tuning anticancer properties and DNA-binding of Pt(ii) complexes via alteration of nitrogen softness/basicity of tridentate ligands

Kamelah S Al-Rashdi; Bandar A Babgi; Ehab M M Ali; Abdesslem Jedidi; Abdul-Hamid M Emwas; Bambar Davaasuren; Mariusz Jaremko; Mark G Humphrey

doi:10.1039/d3ra00395g

Tuning anticancer properties and DNA-binding of Pt(ii) complexes via alteration of nitrogen softness/basicity of tridentate ligands

RSC Adv. 2023 Mar 21;13(14):9333-9346. doi: 10.1039/d3ra00395g. eCollection 2023 Mar 20.

Authors

Kamelah S Al-Rashdi^{1

2}, Bandar A Babgi¹, Ehab M M Ali^{3

4}, Abdesslem Jedidi¹, Abdul-Hamid M Emwas⁵, Bambar Davaasuren⁵, Mariusz Jaremko⁶, Mark G Humphrey⁷

Affiliations

¹ Department of Chemistry, Faculty of Science, King Abdulaziz University P.O. Box 80203 Jeddah 21589 Saudi Arabia bbabgi@kau.edu.sa +966 555563702.
² Department of Chemistry, Al-Qunfudah University College, Umm Al-Qura University Al-Qunfudah 1109 Saudi Arabia.
³ Department of Biochemistry, Faculty of Science, King Abdulaziz University P.O. Box 80203 Jeddah 21589 Saudi Arabia.
⁴ Division of Biochemistry, Department of Chemistry, Faculty of Science, Tanta University Tanta 31527 Egypt.
⁵ Core Labs, King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia.
⁶ Biological and Environmental Science and Engineering (BESE), King Abdullah University of Science and Technology (KAUST) Thuwal 23955-6900 Saudi Arabia.
⁷ Research School of Chemistry, Australian National University Canberra ACT 2601 Australia.

Abstract

Nine tridentate Schiff base ligands of the type (N^N^O) were synthesized from reactions of primary amines {2-picolylamine (Py), N-phenyl-1,2-diaminobenzene (PhN), and N-phenyl-1,2-diaminoethane(EtN)} and salicylaldehyde derivatives {3-ethoxy (OEt), 4-diethylamine (NEt₂) and 4-hydroxy (OH)}. Complexes with the general formula Pt(N^N^O)Cl were synthesized by reacting K₂PtCl₄ with the ligands in DMSO/ethanol mixtures. The ligands and their complexes were characterized by NMR spectroscopy, mass spectrometry and elemental analysis. The DNA-binding behaviours of the platinum(ii) complexes were investigated by two techniques, indicating good binding affinities and a two-stage binding process for seven complexes: intercalation followed by switching to a covalent binding mode over time. The other two complexes covalently bond to ct-DNA without intercalation. Theoretical calculations were used to shed light on the electronic and steric factors that lead to the difference in DNA-binding behavior. The reactions of some platinum complexes with guanine were investigated experimentally and theoretically. The binding of the complexes with bovine serum albumin (BSA) indicated a static interaction with higher binding affinities for the ethoxy-containing complexes. The half maximal inhibitory concentration (IC₅₀) values against MCF-7 and HepG2 cell lines suggest that platinum complexes with tridentate ligands of N-phenyl-o-phenylenediamine or pyridyl with 3-ethoxysalicylimine are good chemotherapeutic candidates. Pt-Py-OEt and Pt-PhN-OEt have IC₅₀ values against MCF-7 of 13.27 and 10.97 μM, respectively, compared to 18.36 μM for cisplatin, while they have IC₅₀ values against HepG2 of 6.99 and 10.15 μM, respectively, compared to 19.73 μM for cisplatin. The cell cycle interference behaviour with HepG2 of selected complexes is similar to that of cisplatin, suggesting apoptotic cell death. The current work highlights the impact of the tridentate ligand on the biological properties of platinum complexes.